CN1301970C - 2,4-Substituted indoles and their use as 5-HT6 modulators - Google Patents

Abstract

The present invention provides compounds of formula , or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹ R²、R³、R⁴P and n are as defined herein. The invention also provides compositions comprising and methods of using and methods of making compounds of formula .

Description

2,4-Substituted indoles and their use as 5-HT6 modulators

The present invention relates to 2-substituted indoles and their related compositions, methods of their use as therapeutic agents and their preparation.

As the main modulatory neurotransmitter in the brain, the neurotransmitter 5-hydroxytryptamine (5-HT) functions by -mediated by a large family of receptors for HT6 and 5-HT7. Based on high levels of 5-HT6 receptor mRNA in the brain, it has been suggested that 5-HT6 receptors may play an important role in the pathology and treatment of central nervous system disorders. Specifically, 5-HT6 selective ligands have been identified as potentially therapeutic for certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorder, Migraine, Alzheimer's disease (enhanced cognitive memory), sleep disorders, eating disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Withdrawal brain syndrome caused by drugs of abuse such as cocaine, alcohol, nicotine and benzodiazepines, schizophrenia and conditions associated with spinal trauma and/or head injury such as hydrocephalus. The compounds are also expected to be useful in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disease. See eg B.L.Roth et al., J.Pharmacol.Exp.Ther., 1994, 268, pp. 1403-14120, D.R.Sibley et al., Mol.Pharmacol., 1993, 43, 320-327, A.J.Sleight et al., Neurotransmission, 1995, 11 , 1-5 and A.J.Sleight et al., Serotonin ID Research Alert, 1997, 2(3), 115-8. 5-HT6 antagonists have also been identified as potentially useful compounds for the treatment of obesity. See, eg, Bentley et al., Br. J. Pharmac. 1999, Suppl. 126; Bently et al., J. Psychopharmacol. 1997, Suppl. A64:255; Wooley et al., Neuropharmacology 2001, 41:210-129; and WO 02/098878.

Although some 5-HT6 modulators have been disclosed, there remains a need for compounds useful for modulating 5-HT6.

One object of the present invention is (i) compounds of formula I:

or a pharmaceutically acceptable salt thereof,

in:

n is 0, 1 or 2;

p is 1 or 2;

^R is optionally substituted aryl or optionally substituted heteroaryl;

^R is optionally substituted heterocyclyl;

R ³ is hydrogen, alkyl, or -C(=O)-R ⁵ , wherein R ⁵ is alkyl, alkoxy, aryl, or aryloxy; and each R ⁴ is independently hydrogen, hydroxyl, cyano , Alkyl, Alkoxy, Thioalkyl, Alkylthio, Halogen, Haloalkyl, Hydroxyalkyl, Nitro, Alkoxycarbonyl, Alkylcarbonyl, Alkylsulfonyl, Arylsulfonyl, Haloalkylsulfonyl Acyl, amino, alkylamino, dialkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonyl amino or methylenedioxy.

The further object of the present invention is:

(ii) the compound of (i),

in:

n is 2;

^R is optionally substituted aryl or optionally substituted heteroaryl;

^R is optionally substituted heterocyclyl;

R ³ is hydrogen, alkyl;

and

^R4 is hydrogen.

(iii) The compound of (ii), wherein R is ^optionally substituted piperazin-1-yl or optionally substituted piperazin-4-yl.

(iv) The compound of (iii), wherein ^R is piperazin-1-yl, 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, N-methylpiperazin Pyridin-4-yl or piperidin-4-yl.

(v) A compound of (iv), wherein R ² is piperazin-1-yl, 4-methylpiperazin-1-yl or piperidin-4-yl.

(vi) The compound of (ii), wherein R ¹ is optionally substituted phenyl or optionally substituted thienyl.

(vii) The compound of (vi), wherein R ¹ is thien-2-yl or phenyl, which is optionally substituted with alkyl, halogen or haloalkyl.

(viii) A compound of (vii), wherein R ^is phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 3-bromo Phenyl or thiophen-2-yl.

(ix) The compound of (ii), wherein R ³ is hydrogen or methyl.

Compounds of (x)(ii), which are:

2-Benzenesulfonyl-4-piperazin-1-yl-1H-indole,

2-Benzenesulfonyl-4-(4-methyl-piperazin-1-yl)-1H-indole,

2-(2,3-dichloro-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-(2,3-dichloro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole,

2-Benzenesulfonyl-1-methyl-4-piperazin-1-yl-1H-indole,

2-(2-fluoro-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-(Toluene-2-sulfonyl)-4-piperazin-1-yl-1H-indole,

2-(2-trifluoromethyl-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-Benzenesulfonyl-4-(3,5-dimethyl-piperazin-1-yl)-1H-indole,

2-(3-Bromo-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-(thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-indole,

2-(2-fluoro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole,

2-(2-fluoro-benzenesulfonyl)-1-methyl-4-piperazin-1-yl-1H-indole,

2-(3-Bromo-benzenesulfonyl)-1-methyl-4-piperazin-1-yl-1H-indole,

2-Benzenesulfonyl-4-piperidin-4-yl-1H-indole.

(xi) Process for the preparation of 2-substituted indoles of formula I:

in:

n is 0, 1 or 2;

p is 1 or 2;

^R is optionally substituted aryl or optionally substituted heteroaryl;

^R is optionally substituted heterocyclyl;

R ³ is hydrogen, alkyl, or -C(=O)-R ⁵ , wherein R ⁵ is alkyl, alkoxy, aryl, or aryloxy; and each R ⁴ is independently hydrogen, hydroxyl, cyano , Alkyl, Alkoxy, Thioalkyl, Alkylthio, Halogen, Haloalkyl, Hydroxyalkyl, Nitro, Alkoxycarbonyl, Alkylcarbonyl, Alkylsulfonyl, Arylsulfonyl, Haloalkylsulfonyl Acyl, amino, alkylamino, dialkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonyl Amino or methylenedioxy;

The methods described include:

Make the substituted indole of formula II:

wherein R ^2' is optionally substituted heterocyclyl optionally protected by a protecting group; R ^3' is alkyl or -C(=O)-R ⁵ ; each R ^4' is independently hydrogen, hydroxyl, Cyano, Alkyl, Alkoxy, Thioalkyl, Alkylthio, Halogen, Haloalkyl, Hydroxyalkyl, Nitro, Alkoxycarbonyl, Alkylcarbonyl, Alkylsulfonyl, Arylsulfonyl, Haloalkane Sulfonyl, amino, alkylamino, dialkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkyl Sulfonylamino or methylenedioxy, optionally protected by a protecting group,

(a) react with a base to generate a deprotonated indole; and

(b) reacting deprotonated indole with a sulfonylating agent of the formula: Y-SO ₂ -R ¹ wherein Y is a halogen or reacting with a disulfide reagent of the formula: R ¹ -SSR ¹ to generate a compound of the formula III 2-Substituted indoles:

(c) optionally oxidizing the sulfur with an oxidizing agent; and

(c) optionally oxidizing the sulfur with an oxidizing agent; and

(d) Optional removal of the protecting group yields a 2-substituted indole of formula I.

(xii) The method of (xi), wherein Y is fluorine.

(xiii) A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I from (i) to (x) and a pharmaceutically acceptable carrier.

(xiv) Use of one or more compounds of any one of (i) to (x) in the preparation of a medicament for treating or preventing a disease state that can be alleviated by a 5-HT6 agonist.

(xv) The use of (xiv), wherein the disease state comprises a CNS disorder.

(xvi) Use of (xv), wherein the disease state includes psychosis, schizophrenia, manic depression, neurological disorders, memory impairment, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease silent disease and Huntington's disease.

(xvii) The use of (xiv), wherein the disease state comprises a gastrointestinal disorder.

(xviii) The use of (xiv), wherein the disease state comprises obesity.

The present invention also provides methods of making compositions comprising compounds of formula I and methods of using compounds of formula I.

Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that as used in the specification and appended claims, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise.

"Agonist" refers to a compound that enhances the activity of another compound or receptor site.

"Alkyl" means a monovalent straight or branched chain saturated hydrocarbon moiety consisting only of carbon and hydrogen atoms, containing 1 to 12, preferably 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkoxy" means a moiety of the formula -OR ^a where R ^a is alkyl as defined herein.

"Antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site.

"Aryl" means a monovalent cyclic arene moiety containing a mono- or bicyclic aromatic ring. Unless otherwise specified, aryl may be optionally substituted by 1, 2 or 3, preferably 1 or 2, substituents, each of which is independently hydroxyl, cyano, alkyl, alkoxy, Thioalkyl, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, amino, alkylamino, Dialkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonylamino or methylenedioxy. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, optionally substituted naphthyl, and the like.

"Aryloxy" means a moiety of the formula ^-ORb wherein ^Rb is aryl as defined herein.

"Cycloalkyl" means a monovalent saturated carbocyclic moiety containing a single or bicyclic ring. Unless otherwise specifically indicated, cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkyl amino or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Disease state" means any disease, disorder, symptom or indication.

The terms "halo" and "halogen" are used interchangeably herein to refer to a substituent of fluorine, chlorine, bromine or iodine, preferably fluorine or bromine.

"Haloalkyl" means an alkyl group as defined herein in which one or more hydrogens has been replaced by the same or a different halogen. Examples of haloalkyl include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , perfluoroalkyl (eg -CF ₃ ), and the like.

"Heteroaryl" means a monovalent mono-, di- or a three-ring aromatic moiety. The heteroaryl ring is optionally substituted independently by one or more substituents, preferably one or two substituents selected from the group consisting of hydroxy, cyano, alkyl, alkoxy, thio Alkyl, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, amino, alkylamino, dioxane alkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonylamino or methylenedioxy. More specifically, the term "heteroaryl" includes, but is not limited to, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, Pyrimidinyl, benzofuryl, isobenzofuryl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoxindenyl, benzoxazolyl, quinolinyl, Isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothienyl, dibenzofuran, benzodiazepine-2-on-5-yl, and the like.

"Heterocyclyl" means a monovalent saturated moiety containing 1 to 3 rings containing 1, 2 or 3 heteroatoms (selected from nitrogen, oxygen or sulfur). The ring of the heterocyclyl group is optionally substituted independently by one or more substituents, preferably one or two substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, thioalkane radical, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, amino, alkylamino, dialkyl Amino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonylamino or methylenedioxy. More specifically, the term "heterocyclyl" includes, but is not limited to (examples of heterocyclyl moieties include but are not limited to) morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, nitrogen Heterocyclobutane (azitidinyl) and the like.

"Leaving group" means a group with the meaning usually associated therewith in synthetic organic chemistry, ie, an atom or group that is displaceable under substitution reaction conditions. It should be understood that the particular leaving group depends on the reaction conditions, including the atom to which the leaving group is attached. For example, leaving groups of sulfonyl compounds include, but are not limited to, halogens, sulfonic acid groups, and the like.

"Modulator" means a molecule that interacts with a target. Said interactions include, but are not limited to, agonists, antagonists, etc. as defined herein.

"Optional" or "optionally" means that the subsequently described event or condition can occur but need not occur, and that the description includes instances where the event or condition occurs and instances where it does not.

"Inert organic solvent" or "inert solvent" means that the solvent is inert under the reaction conditions related thereto, and the solvent includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformaldehyde Amide, chloroform, dichloromethane, dichloroethane, ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc. Unless otherwise stated, the solvents used in the reactions of the present invention are all inert solvents.

"Pharmaceutically acceptable" means useful in the preparation of pharmaceutical compositions which are generally safe, non-toxic, and free from biological and other undesirable properties, and which are suitable for veterinary and human pharmaceutical use. are acceptable.

"Pharmaceutically acceptable salt" of a compound means a pharmaceutically acceptable salt, as defined herein, which possesses the desired pharmacological activity of the parent compound. Such salts include:

Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid Acid, Glucoheptonic Acid, Gluconic Acid, Glutamic Acid, Glycolic Acid, Hydroxynaphthoic Acid, 2-Hydroxyethanesulfonic Acid, Lactic Acid, Maleic Acid, Malic Acid, Malonic Acid, Mandelic Acid, Methanesulfonic Acid, Muconic Acid acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, trimethylacetic acid, etc.; or

Salts formed when an acidic proton present in a parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth metal ion or aluminum ion or coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglutamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are those formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the acid addition salt as defined herein.

"Prodrug" or "prodrug" means a pharmacologically inactive form of a compound that must, after administration, be metabolized to a pharmacologically active form of the compound within the body of the subject, e.g., by biological fluids or enzymes, to produce the desired pharmacological effects. Prodrugs can be metabolized before absorption, during absorption, after absorption, or at specific sites. Although the metabolism of many compounds occurs primarily in the liver, virtually all other tissues and organs, especially the lungs, metabolize to varying degrees. Prodrug forms of the compounds may be used, for example, to increase bioavailability, improve acceptability to the subject of administration, e.g. by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritation, alter solubility e.g. for intravenous use , provide prolonged or sustained release or delivery, increase ease of formulation, or provide localized delivery of the compound. References to compounds herein include prodrug forms of the compounds.

"Protecting group" or "protecting group" means, in the meaning usually associated with it in synthetic chemistry, the ability to selectively block one reactive site in a polyfunctional compound in order to allow chemical reactions to occur selectively at another unprotected The group carried out on the reactive site. Certain processes of the present invention rely on protecting groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein to refer to those organic groups intended to prevent undesired reactions of the nitrogen atom during synthetic procedures. Examples of nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (benzyloxycarbonyl, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), etc. Similarly, the term "hydroxyl protecting group" refers to those organic groups intended to prevent undesired reactions of the oxygen atom of the hydroxy group during synthetic procedures. Examples of hydroxy protecting groups include, but are not limited to, benzyl, silyl, tetrahydropyranyl, ester, and the like. Those skilled in the art know how to choose groups that are easy to remove and withstand subsequent reactions.

"Solvate" means a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state to form solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates may be formed by combining one or more molecules of water with a molecule of a substance, wherein the water retains its molecular state _H2O , said combination being capable of forming one or more hydrates.

"Subject" means mammals and non-mammals. Mammal means any member of the mammalian class including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkeys, farm animals such as cows, horses, sheep, goats and pigs, livestock such as rabbits, Dogs and cats, laboratory animals including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds and the like. The term "administration subject" does not indicate specific age and sex.

"Therapeutically effective amount" means an amount of a compound which, when administered to a subject to treat a disease state, is sufficient to effect treatment of the disease state. The "therapeutically effective amount" will vary depending on factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject to be administered, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

The terms "those defined above" and "those defined herein" when referring to a variable include the broad definition as well as the preferred, more preferred and most preferred definitions (if any) of the variable.

"Treatment" of a disease state or "treatment" of a disease state includes:

(i) preventing a disease state, ie, preventing the development of clinical symptoms of a disease state in a subject of administration who may be exposed to or susceptible to the disease state but has not yet experienced or exhibited symptoms of the disease state.

(ii) inhibit the disease state, i.e., arrest the development of the disease state or its clinical symptoms, or

(iii) Alleviation of the disease state, ie, temporary or permanent regression of the disease state or its clinical symptoms.

The terms "treating", "contacting" and "reacting" when referring to a chemical reaction mean adding or mixing two or more reagents under suitable conditions to produce the described and/or desired product. It should be understood that the reaction leading to the described and/or desired product may not necessarily be the direct result of the mixing of the two initially added reagents, i.e. there may be one or more intermediates formed in the mixture which eventually lead to the described and/or desired product formation.

In general, nomenclature used in this application is based on AUTONOM ^(TM) Version 4.0, the Beilstein Institute computer system used to generate IUPAC systematic nomenclature.

In one aspect, the invention provides compounds of formula I:

its pharmaceutically acceptable salt or prodrug,

in:

n is 0, 1 or 2; preferably n is 2;

p is 1 or 2, preferably p is 1;

R ¹ is aryl or heteroaryl;

R ² is a heterocyclic group;

R ³ is hydrogen, alkyl, or -C(=O)-R ⁵ , wherein R ⁵ is alkyl, alkoxy, aryl, or aryloxy; and each R ⁴ is independently hydrogen, hydroxyl, cyano , Alkyl, Alkoxy, Thioalkyl, Alkylthio, Halogen, Haloalkyl, Hydroxyalkyl, Nitro, Alkoxycarbonyl, Alkylcarbonyl, Alkylsulfonyl, Arylsulfonyl, Haloalkylsulfonyl Acyl, amino, alkylamino, dialkylamino, alkyl(aryl)amino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl(alkylamino), alkylaminosulfonyl, alkylsulfonyl Amino or methylenedioxy; preferably ^R4 is hydrogen, alkyl, alkoxy, halogen or haloalkyl.

It should be understood that the scope of the present invention includes not only the various isomers that may exist, but also the mixtures of various isomers that may be formed. Furthermore, solvates and salts of the compounds of formula I are also within the scope of the present invention.

Preferably, R ¹ is thienyl or phenyl, which is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, -SO ₂ -R ^a , -NR ^a R ^b , -NR ^b -C(=O)-R ^a , wherein R ^a is alkyl or aryl, and R ^b is hydrogen or alkyl, and combinations thereof. More preferably, R ^is thiophen-2-yl, phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl or 3-bromo phenyl.

Preferably, R ² is optionally substituted piperazinyl or piperidinyl. More preferably, ^R is optionally substituted piperazin-1-yl or piperidin-4-yl. Still more preferably, R ^is piperazin-1-yl, 4-methylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, N-methylpiperidin-4-yl or piperidin-4-yl. In a specific embodiment, R ² is 4-methylpiperazin-1-yl.

Preferably, ^R3 is hydrogen or methyl.

Preferably, ^R4 is hydrogen.

Still further, combinations of the preferred groups described herein will form other preferred embodiments.

For example, in a particularly preferred embodiment, ^R1 is phenyl, n is 2, ^R2 is piperazin-1-yl, ^R3 is hydrogen or methyl, and ^R4 is hydrogen. In this manner, the present invention can form a variety of preferred compounds.

Some representative compounds of formula I are shown in Table 1 below:

Table 1. Representative Compounds of Formula I

Another aspect of the invention provides compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.

Another aspect of the present invention provides a method of treating a CNS disease state in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I. Preferably, said disease states include psychosis, schizophrenia, manic depression, neurological disorders, memory impairment, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease sick.

Another aspect of the present invention provides a method of treating a gastrointestinal disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I.

In addition, another aspect of the present invention provides a method for treating obesity in a subject, the method comprising administering a therapeutically effective amount of a compound of formula I to the subject.

Another aspect of the invention provides processes for the preparation of compounds of formula I.

Compounds of the present invention can be prepared by a variety of methods and described in the exemplary synthetic reaction schemes shown and described below.

Starting materials and reagents for the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co. or can be obtained from references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, vol. 1-15 Rodd'sChemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5 and supplements; and Organic Reactions, Wiley & Sons: New York, 1991, operations given in volumes 1-40 are well known to those skilled in the art Method preparation. The following synthetic reaction schemes are only an illustration of some methods that can be used to synthesize the compounds of the present invention, and various modifications can be made to these synthetic reaction schemes. After referring to the disclosure contained in the application, those skilled in the art can know that Inspiration for these modifications.

If necessary, the starting materials and intermediates in the synthesis reaction scheme can be separated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. These substances can be characterized using conventional methods including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure at a temperature of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, most preferably and conveniently at about room temperature (or ambient temperature) eg at a reaction temperature of about 20°C.

In one embodiment, compounds of formula I are preferably prepared by deprotonating a substituted indole of formula II with a base:

And add a sulfonylating agent of the formula: Y-SO ₂ -R ¹ , wherein R ¹ , R ² and R ⁴ are as defined herein, R ^3' is an alkyl group or -C(=O)-R ⁵ , wherein R ⁵ As defined herein, and Y is a leaving group, preferably halogen, more preferably fluoro. It should be understood that when ^R2 and/or ^R4 have one or more acidic protons (relative to the base used), they should be protected with a suitable protecting group. Suitable protecting groups for the acidic proton are well known to those skilled in the art and depend on the nature of the acidic proton, eg whether it is an amino or hydroxyl proton, etc.

The base should be strong enough to deproton primarily the 2-position of the indole ring system. Such bases are well known to those skilled in the art and include organometallic compounds such as organolithium eg tert-butyllithium and Grignard reagents eg tert-butylmagnesium halide. Typically, the deprotonation reaction is carried out at a temperature of about 0°C or below, preferably at about -40°C or below, more preferably at about -70°C or below. Typically, the deprotonation reaction is carried out at about -75°C.

Suitable sulfonylating agents include arylsulfonyl halides such as arylsulfonyl fluoride. Arylsulfonyl fluorides are readily prepared from the corresponding arylsulfonyl chlorides by treatment with a fluoride source such as potassium fluoride or other suitable metal fluoride. Typically, the conversion of the arylsulfonyl chloride to its corresponding fluoride derivative involves reacting the arylsulfonyl chloride with potassium fluoride in an inert organic solvent such as 1,4-dioxane. The reaction is generally carried out at reflux for about 1 to about 48 hours, typically about 24 hours. Usually, an excess of potassium fluoride is used in the reaction, which can be conveniently removed by washing with water in the workup. Typically, the resulting arylsulfonyl fluoride is used directly without any further purification.

Alternatively, compounds of formula I can also be prepared by reacting a deprotonated indole group with a disulfide reagent of formula: R ¹ -SSR ¹ to form a thioether of formula III:

wherein R ¹ , R ² , R ^3′ and R ⁴ are as defined herein. Typically, the disulfide reagent is added to the deprotonated indole at the same temperature as the base. The reaction mixture is then stirred at this temperature for several minutes to several hours, typically about 1 to 2 hours, and allowed to gradually warm to room temperature.

Thioether compounds of formula III can be oxidized with an oxidizing agent to form the corresponding sulfoxides and/or sulfones. Suitable oxidizing agents include m-chloroperbenzoic acid (MCPBA), periodic acid or periodate, potassium persulfate (Oxone( ^R )), and other sulfur oxidizing agents known to those skilled in the art. For example, thioether III can be reacted with MCPBA by combining the two reagents at about 0°C in an inert solvent such as dichloromethane and stirring the mixture at room temperature for several hours. Typically, excess MCPBA is removed by washing with an aqueous solution, preferably an aqueous alkaline solution. Any undesired oxidation of nitrogen atoms can be reduced by quenching the crude product with a phosphine compound such as triphenylphosphine.

When the ^R1 or ^R2 groups contain protecting groups, or when R3 ^' is a protecting group, these protecting groups can be removed after synthesis using reaction conditions routinely known to those skilled in the art. See, eg, Protective Groups in Organic Synthesis, 3rd Edition, TW Greene and PGM Wuts, John Wiley & Sons, New York, 1999, which is hereby incorporated by reference in its entirety.

More specific details for the preparation of compounds of formula I are described in the Examples section.

Surprisingly and unexpectedly, the present inventors have found that indole compounds having a substituent -S(O) _nR1 at the 2-position have a variety of ^{pharmacological} activities, while none at the 2-position. The corresponding indoles with the above substituents do not have these pharmacological activities. For example, the compounds of the present invention have selective 5-HT6 receptor affinity and are useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy , obsessive-compulsive disorder, migraine, Alzheimer's disease (cognitive memory enhancement), sleep disorders, eating disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Withdrawal brain syndrome caused by drugs of abuse such as cocaine, alcohol, nicotine and benzodiazepines, schizophrenia and conditions associated with spinal trauma and/or head injury such as hydrocephalus. In addition, the compounds of the present invention are also useful in the treatment of certain GI (gastrointestinal) disorders, such as functional bowel disease.

The pharmacology of the compounds of the present invention can be determined by methods recognized in the art. In vitro techniques for determining the affinity of test compounds for the 5-HT6 receptor in radioligand binding and functional assays are described in Examples 4-6.

The present invention includes pharmaceutical compositions comprising at least one compound of the present invention or a single isomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof and at least one A pharmaceutically acceptable carrier and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances exerting similar effects. Suitable dosage ranges are typically 1-500 mg per day, preferably 1-100 mg per day, most preferably 1-30 mg per day, depending on factors such as the severity of the disease being treated, the age and relative health of the subject, the The potency of the compound, the route and form of administration, the indications for which it is administered, and the preference and experience of the relevant medical practitioner. A therapeutically effective amount of a compound of the invention for a given disease can be determined by one of ordinary skill in the art of treating such disease without undue experimentation relying on personal knowledge and the disclosure of this application.

Typically, the compounds of the invention are administered in pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial , intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral, using a suitable daily dosage regimen which can be adjusted according to the severity of the affliction.

One or more compounds of the invention can be placed in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. Pharmaceutical compositions and unit dosage forms may contain the ingredients in conventional proportions, with or without additional active compounds or ingredients, and unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range employed. The application form of the pharmaceutical composition may be solid such as tablet or filled capsule, semi-solid, powder, sustained release preparation or liquid such as solution, suspension, emulsion, elixir or filled capsule for oral use; or with In the form of a suppository for rectal or vaginal administration; or as a sterile injectable solution for parenteral use. Accordingly, formulations containing from about 1 mg of active ingredient, or more broadly, from about 0.01 to about 100 mg of active ingredient per tablet, are suitable representative unit dosage forms.

The compounds of the present invention can be formulated in various dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain as an active ingredient one or more compounds of the present invention, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is in a mixture with the finely divided active ingredient. In tablets, the active ingredient usually is mixed with the carrier having the necessary binding capabilities in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1% to about 70% active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter, etc. The term "preparation" is intended to include the formulation of the active compound which contains encapsulating material as carrier to provide a capsule in which the active ingredient, with or without carriers, is surrounded by the carrier in association with it. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges are all solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations (including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions) or solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in solutions, such as aqueous propylene glycol solutions, or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Liquid form preparations include solutions, suspensions, and emulsions, which may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents , solubilizer, etc.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, prefilled syringes, small volume infusion solutions or Available in multi-dose containers with added preservatives. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil) and organic esters for injection (such as ethyl oleate), and may contain formulation substances such as preservatives agent, wetting agent, emulsifying or suspending agent, stabilizing agent and/or dispersing agent. Alternatively, the active ingredient may be in powder form, obtained by aseptic dispensing of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, eg, sterile, pyrogen-free water.

The compounds of the invention may be formulated for topical application to the epidermis in ointments, creams or lotions, or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and generally also contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia. ingredients; and mouthwashes containing the active ingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration in the form of suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, can be first melted and the active ingredient dispersed homogeneously, eg by stirring. The molten homogeneous mixture is then poured into suitably sized molds, allowed to cool and solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient carriers well known in the art are suitable.

The compounds of the invention may be formulated for nasal administration. Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be in single or multiple dose form. For multiple dose forms with a dropper or pipette, this can be accomplished by the patient administering an appropriate, predetermined volume of the solution or suspension. For nebulizers, this can be achieved, for example, by means of metered atomizing spray pumps.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds typically have a small particle size, for example on the order of 5 microns or less. Said particle size can be obtained by methods known in the art, for example by micronization. The active ingredient is supplied in pressurized packs containing a suitable propellant such as a chlorofluorocarbon (CFC), eg, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosols may also suitably contain surfactants such as lecithin. Drug dosage can be controlled by a metered valve. Alternatively, the active ingredient may be presented in dry powder form, for example as a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. Powder compositions may be presented in unit dosage form, for example, as gelatin capsules or cartridges or blister packs from which the powder may be administered by means of an inhaler.

Formulations can be prepared, if desired, with enteric coatings suitable for slow or controlled release administration of the active ingredient. For example, the compounds of the invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. Compounds in transdermal delivery systems are often attached to a skin-adhesive solid carrier. Compounds of interest may also be used in combination with penetration enhancers, such as laurocaprine (1-dodecylazepan-2-one). Sustained release delivery systems can be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a liquid soluble membrane such as silicone rubber or a biodegradable polymer such as polylactic acid.

The pharmaceutical formulations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th ed., Easton, Pennsylvania. Representative pharmaceutical formulations containing compounds of the invention are described in Examples 6-12.

Example

The purpose of giving the following preparation methods and examples is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limitations on the scope of the invention, but merely as illustrative and representative examples thereof.

Example 1

This example illustrates the preparation of compounds of formula I using the synthetic scheme described below.

     2-(2-Fluoro-benzenesulfonyl)-4-piperazin-1-yl-1H-indole

step 1

To a solution of indole 1-1 (1.38 g, 4.6 mmol) in THF (35 ml) at room temperature was added di-tert-butyl dicarbonate (1.0 g, 4.6 mmol) followed by DMAP (56 mg, 0.46 mmol) . The reaction mixture was stirred at room temperature under nitrogen for 1 hour, then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50ml). The organic layer was washed with saturated sodium bicarbonate solution (2 x 25ml), then brine (25ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to a clear oil. The oil was crystallized from hexane to afford 1.65 g (89%) of tert-butoxycarbonyl-piperazine tert-butoxycarbonyl-indole (1-2) as a white solid. (M+H) ⁺ = 402.2.

Step 2a

Potassium fluoride (99%) (12 g, 216 mmol) was added to a solution of 2-fluorobenzenesulfonyl chloride (10 g, 51 mmol) in 1,4-dioxane (35 ml). The reaction mixture was refluxed for 24 hours. It was then cooled to room temperature and poured into ice water (200ml). The ice water was extracted with chloroform (3 x 50ml). The combined chloroform layers were dried ( _MgSO4 ), filtered and concentrated to afford 2-fluorobenzenesulfonyl fluoride (2a) as a colorless oil 6.7g (74%). (M+H) ⁺ =177.

step 2

To a solution of bis-tert-butoxycarbonyl-indole 2 (500 mg, 1.25 mmol) in THF (25 ml) at -75°C was slowly added t-BuLi (1.47 ml, 2.5 mmol). The reaction mixture was stirred for 30 minutes, then 2-fluorobenzenesulfonyl fluoride 2a (222 mg, 1.5 mmol) was added. The reaction was stirred for 1.5 hours, then the ice bath was removed and the reaction was allowed to warm for 45 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (55 ml). The mixture was then extracted with ethyl acetate (3 x 20ml). The combined ethyl acetate layers were washed with brine (25ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to a yellow oil. The oil was chromatographed on silica gel eluting with hexane:ethyl acetate (17:3) to afford 300 mg (43%) of 2-phenylsulfonyl-4-piperazin-1-ylindole ( 1-3).

step 3

2-Phenylsulfonyl-4-piperazin-1-ylindole (1-3) (300mg, 0.54mmol) was dissolved in 1M HCl in ethanol (30ml) and heated to reflux. After 2.5 hours the reaction mixture was cooled to room temperature and diethyl ether (30ml) was added. The gray precipitate was collected to yield 150 mg (65%) of the dihydrochloride salt of product (6). (M+H) ⁺ =360.

Similarly, compounds 1, 3, 7, 8, 9, 10 and 11 in Table 1 above were synthesized in the same manner as above:

2-Benzenesulfonyl-4-piperazin-1-yl-1H-indole,

2-(2,3-dichloro-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-(Toluene-2-sulfonyl)-4-piperazin-1-yl-1H-indole,

2-(2-trifluoromethyl-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-Benzenesulfonyl-4-(3,5-dimethyl-piperazin-1-yl)-1H-indole,

2-(3-Bromo-benzenesulfonyl)-4-piperazin-1-yl-1H-indole,

2-(thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-indole.

Example 2

This example illustrates a method for alkylating the piperazine moiety of a compound of formula I.

  2-Benzenesulfonyl-4-(4-methyl-piperazin-1-yl)-1H-indole

To a solution of the free base of compound 1 in Table 1 (269 mg, 0.79 mmol) and formaldehyde (30%) (0.3 ml, 3.97 mmol) in THF (20 ml) under an inert atmosphere was added triacetoxyboron in one portion Sodium hydride (250 mg, 1.2 mmol). The reaction was stirred at room temperature for 24 hours, then concentrated in vacuo. The residue was partitioned between 1M sodium hydroxide (25ml) and ethyl acetate (25ml). The aqueous layer was extracted with ethyl acetate (2 x 15ml). The combined organic layers were dried ( _MgSO4 ), filtered and concentrated. The remaining oil was chromatographed on silica gel eluting with dichloromethane/methanol (5:1) to give the product as a clear oil (140mg, 0.39mmol). The TFA salt of the oil was prepared by dissolving the oil in dichloromethane (10 ml) and adding TFA (90 mg, 0.79 mmol). Dichloromethane was concentrated and the remaining oil was crystallized from ethanol to give 110 mg (39%) of compound 2 in Table 1. M+H=356.

Similarly, compounds 4 and 12 in Table 1 above were synthesized in the same manner as above:

2-(2,3-dichloro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole,

2-(2-Fluoro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole.

Example 3

This example illustrates another method for preparing compounds of formula I.

2-Benzenesulfonyl-1-methyl-4-piperazin-1-yl-1H-indole

step 1

To a solution of indole 1-1 (500 mg, 1.7 mmol) in THF (20 ml) under nitrogen was added potassium tert-butoxide (223 mg, 2.0 mmol). The reaction was stirred for 30 minutes, then iodomethane (0.16ml, 2.5mmol) was added. The reaction was stirred for 3 hours then quenched with water (20ml) and extracted with ethyl acetate (2x30ml). The ethyl acetate layer was washed with brine (25ml), dried ( _MgSO4 ), filtered and concentrated to give a green oil (540mg, 1.6mmol). The oil was chromatographed on silica gel, eluting with ethyl acetate/hexane (1:6), to afford 420 mg (80%) of compound 3-1 as a white solid. M+H=316.

step 2

To a solution of N-methylindole compound 3-1 (330 mg, 1.05 mmol) in THF (25 ml) at -75°C was slowly added t-BuLi (1.2 ml, 2.1 mmol). The reaction mixture was stirred at -75°C for 30 minutes, then warmed in an ice bath for 15 minutes. The reaction was cooled again to -75°C and benzenesulfonyl fluoride (0.2ml, 1.6mmol) was added. The reaction was stirred with cooling for 1.5 hours, then the ice bath was removed and the reaction was allowed to warm to room temperature (45 minutes). The reaction was quenched with saturated ammonium chloride solution (55ml) and extracted with ethyl acetate (3 x 20ml). The combined ethyl acetate layers were washed with brine (25ml), dried ( _MgSO4 ), filtered and concentrated to give a yellow oil. The oil was chromatographed on silica gel eluting with hexane/ethyl acetate (4:1) to afford 190 mg (40%) of product (3-2).

step 3

Indole 3-2 (190mg, 0.54mmol) was dissolved in 1M HCl in ethanol (30ml) and heated to reflux. After 2.5 hours, the reaction mixture was cooled to room temperature and diethyl ether (30ml) was added. The white precipitate was collected to yield 130 mg (87%) of the dihydrochloride salt of compound 5 in Table 1 . M+H=356.

Similarly, compounds 13 and 14 in the above Table 1 were synthesized in the same manner as above:

2-(2-fluoro-benzenesulfonyl)-1-methyl-4-piperazin-1-yl-1H-indole,

2-(3-Bromo-benzenesulfonyl)-1-methyl-4-piperazin-1-yl-1H-indole.

Example 4

This example illustrates the preparation of compounds of formula I wherein ^R is piperidin-4-yl using the synthetic scheme described below:

                                                             

step 1

Di-tert-butyl dicarbonate (17 g, 76.5 mmol) was added to a solution of 4-bromoindole 4-1 (10 g, 51 mmol) and DMAP (0.62 g, 0.51 mmol) in THF (120 ml). The reaction mixture was stirred for 15 minutes, then the volatile components were removed. The remaining oil was partitioned between ether and water. The ether layer was washed with 3 x 50 ml saturated sodium bicarbonate and 1 x 75 ml brine. The ether layer was dried over magnesium sulfate, filtered and the volatile components were removed. The remaining brown oil was chromatographed on silica gel eluting with 1:100 ethyl acetate/hexanes to afford 15 g (100% yield) of tert-butyl 4-bromo-indole-1-carboxylate 4- 2.

step 2

A solution of 4-bromo-indole-1-carboxylic acid-tert-butyl ester 4-2 (4.9 g, 16.5 mmol) in THF (150 ml) under argon was cooled to -70 °C and n was added over 20 min. - BuLi (12.4ml, 24.8mmol). The reaction mixture was warmed to -5°C in an ice bath and stirred at this temperature for 30 minutes. The mixture was cooled to -70°C and a solution of N-tert-butoxycarbonyl-piperidone 4-3 (3.3 g, 16.5 mmol) in THF (10 ml) was added within 15 minutes. The reaction was stirred at -70°C for 45 minutes and then allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride solution (75ml) and partitioned between water (25ml) and ethyl acetate (75ml). The organic layer was washed with water (50ml) and brine (50ml), then dried ( _MgSO4 ), filtered and concentrated. The remaining brown oil was chromatographed eluting with ethyl acetate:hexane (1:9) to afford 1.32 g (19% yield) of 4-(1-tert-butoxycarbonyl-4-hydroxy-piperidine -4-yl)-tert-butyl indole-1-carboxylate 4-4.

step 3

4-(1-tert-butoxycarbonyl-4-hydroxy-piperidin-4-yl)-indole-1-carboxylic acid tert-butyl ester 4-4 (1.32 g, 3.17 mmol) was placed under house vacuum (house vaccum) Heat to 180°C until bubbling stops. The reaction mixture was cooled and solidified to give tert-butyl 4-hydroxy-4-(1-H-indol-4-yl)-piperidine-1-carboxylate (1.0 g, 100% yield) 4-5.

step 4

At room temperature, under nitrogen, 4-hydroxy-4-(1-H-indol-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 4-5 (1.0g, 3.17mmol) and pyridine (20ml) Combine with phosphorus oxychloride (0.7ml, 7.4mmol) and stir overnight. The reaction was partitioned between ethyl acetate (55ml) and water (55ml). The ethyl acetate layer was washed with water (2 x 30ml) and brine (55ml), then dried ( _MgSO4 ), filtered and concentrated to afford (670mg, 71%) 4-(1H-indol-4-yl)-3, tert-Butyl 6-dihydro-2H-pyridine-1-carboxylate 4-6.

step 5

4-(1H-indol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 4-6 (670 mg, 2.24 mmol) and 10% Pd/C (70 mg) in The mixture in ethanol (75ml) was placed on a parr shaker at 50psi under H2 atmosphere and shaken overnight. The reaction mixture was filtered through a Celite plug topped with glass filter paper. The filtrate was concentrated to afford (650 mg, 96%) tert-butyl 4-(1H-indol-4-yl)-piperidine-1-carboxylate 4-7.

step 6

To a solution of tert-butyl 4-(1H-indol-4-yl)-piperidine-1-carboxylate 4-7 (650 mg, 2.16 mmol) in THF (75 ml) at room temperature was added di-tert-dicarbonate Butyl ester (519 mg, 2.38 mmol), followed by catalytic amount of DMAP (5.6 mg, 0.046 mmol). The reaction mixture was stirred at room temperature under nitrogen for 24 hours, then the reaction mixture was freed of volatile components. The residue was partitioned between ethyl acetate (50ml) and saturated sodium bicarbonate (50ml). The organic layer was washed with saturated sodium bicarbonate (2 x 25ml), brine (25ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated to a clear oil. The oil was chromatographed eluting with hexane/ethyl acetate (23:1) to give 470 mg (54%) of 4-(1-tert-butoxycarbonyl-piperidin-4-yl)-indole- 1-tert-butyl carboxylate 4-8.

step 7

To a solution of 4-(1-tert-butoxycarbonyl-piperidin-4-yl)-indole-1-carboxylic acid tert-butyl ester 4-8 (470mg, 1.2mmol) in THF (20ml) at -75°C t-BuLi (1.6ml, 2.25mmol) was added slowly. The reaction mixture was stirred at -75°C for 45 minutes and benzenesulfonyl fluoride 2a (0.22ml, 1.8mmol) was added. The reaction was stirred for 2.5 hours, then the ice bath was removed, the reaction was allowed to warm to room temperature and quenched with saturated ammonium chloride solution (25ml). Then, the mixture was extracted with ethyl acetate (3 x 20ml). The combined ethyl acetate layers were washed with brine (25ml), dried ( _MgSO4 ), filtered and the volatile components were removed to give a yellow oil. The oil was chromatographed on silica gel eluting with hexane/ethyl acetate (4:1) to give (310 mg, 60%) the product 2-benzenesulfonyl-4-(1-tert-butoxycarbonyl- Piperidin-4-yl)-indole-1-carboxylic acid tert-butyl ester 4-9.

Step 8

Dissolve tert-butyl 2-benzenesulfonyl-4-(1-tert-butoxycarbonyl-piperidin-4-yl)-indole-1-carboxylate 4-9 (310 mg, 0.57 mmol) in 1M HCl in ethanol (30ml) and heated to reflux. After 2.5 hours, the reaction mixture was cooled to room temperature and diethyl ether (30ml) was added. The white precipitate was collected to give 138 mg (64%) of the product 2-benzenesulfonyl-4-piperidin-4-yl-1H-indole 15.

Example 5

This example illustrates in vitro radioligand binding studies of compounds of formula I.

The in vitro binding activity of the compounds of the present invention was determined as follows. Ligand affinity assays were performed in duplicate by competitive binding of [ ^3H ]LSD in cell membranes derived from HEK293 cells stably expressing the recombinant human 5-HT6 receptor.

All assays were performed at 37°C in a reaction volume of 250 microliters in assay buffer containing 50 mM Tris-HCl, 10 mM _MgSO4 , 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4. Incubate the test tube containing [ ³ H]LSD (5nM), competing ligand and cell membrane at 37°C for 60 minutes in a shaking water bath, and filter to PackardGF-B plate (with 0.3% PEI pre-soaked), and washed 3 times with ice-cold 50mM Tris-HCl. Incorporated [ ^3H ]LSD was measured in radioactivity counts per minute using a Packard TopCount.

[ ³ H]LSD displacement from the binding site was quantified by fitting the concentration-binding data to a 4-parameter logarithmic equation:

where Hill is the Hill slope, [ligand] is the concentration of competing radioligand, and _IC50 is the concentration of radioligand that produces half the maximum specific binding of the radioligand. The specific binding window is the difference between Bmax and the background parameter.

Using the method of Example 4, compounds of formula I were tested and found to be selective 5-HT6 antagonists. Representative material activities are shown in Table 2.

Table 2 Binding data of radioligands serial number name pK 1 2-Benzenesulfonyl-4-piperazin-1-yl-1H-indole 9.9 2 2-Benzenesulfonyl-4-(4-methyl-piperazin-1-yl)-1H-indole 9.9 5 2-Benzenesulfonyl-1-methyl-4-piperazin-1-yl-1H-indole 9.7 9 2-Benzenesulfonyl-4-(3,5-dimethyl-piperazin-1-yl)-1H-indole 9.1 12 2-(2-Fluoro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole 9.9 14 2-(3-Bromo-benzenesulfonyl)-1-methyl-4-piperazin-1-yl-1H-indole 9.3

Example 6

The cognition-enhancing properties of the compounds of the invention can be demonstrated in an animal cognition model: the object cognition model. 4-month-old male Wistar rats (Charles River, Netherlands) were used. Compounds were prepared daily, dissolved in saline, and tested at 3 doses. Administration was always performed intraperitoneally 60 minutes before T1 (injection volume 1 ml/kg). Scopolamine hydrobromide was injected 30 minutes after compound injection. Two identical test groups consisted of 24 rats and were tested by two experimenters. The order of trials with doses was determined randomly. Experiments were performed using a double-blind protocol. All rats were treated once with each dosage condition. Object recognition was performed as described in Ennaceur, A., Delacour, J., 1988, A new one-off test for the neurobiology of memory in rats. 1: Behavioral data. Behav. Brain Res. 31, 47-59 knowledge test.

While the invention has been described in terms of specific embodiments thereof, it will be understood by those skilled in the art that various changes and equivalents may be made without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular condition, material, composition of matter, method, method step or steps to be within the objective spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (16)

1. the compound of formula I:

Or its pharmacologically acceptable salt,

Wherein:

N is 1 or 2;

P is 1 or 2;

R ¹Be phenyl or thienyl, it is chosen wantonly and is replaced by one or more substituting groups, and described substituting group is selected from C ₁-C ₁₂Alkyl, halogen, halo C ₁-C ₁₂Alkyl;

R ²Be piperazinyl or piperidyl, it is optional by one or more C ₁-C ₁₂Alkyl replaces;

R ³Be hydrogen, C ₁-C ₁₂Alkyl; And

Each R ⁴Be hydrogen independently.

2. the compound of claim 1,

Wherein:

N is 2.

3. the compound of claim 2, wherein said piperazinyl is piperazine-1-base, described piperidyl is a piperidin-4-yl.

4. the compound of claim 3, wherein R ²Be piperazine-1-base, 4-methylpiperazine-1-base, 3,5-lupetazin-1-base, N-methyl piperidine-4-base or piperidin-4-yl.

5. the compound of claim 4, wherein R ²Be piperazine-1-base, 4-methylpiperazine-1-base or piperidin-4-yl.

6. the compound of claim 2, wherein R ¹Be phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 2-aminomethyl phenyl, 2-trifluoromethyl, 3-bromophenyl or thiophene-2-base.

7. the compound of claim 2, wherein R ³Be hydrogen or methyl.

8. the compound of claim 2, it is:

2-benzenesulfonyl-4-piperazine-1-base-1H-indoles,

2-benzenesulfonyl-4-(4-methyl-piperazine-1-yl)-1H-indoles,

2-(2,3-two chloro-benzenesulfonyls)-4-piperazine-1-base-1H-indoles,

2-(2,3-two chloro-benzenesulfonyls)-4-(4-methyl-piperazine-1-yl)-1H-indoles,

2-benzenesulfonyl-1-methyl-4-piperazine-1-base-1H-indoles,

2-(2-fluoro-benzenesulfonyl)-4-piperazine-1-base-1H-indoles,

2-(Toluene-2,4-diisocyanate-alkylsulfonyl)-4-piperazine-1-base-1H-indoles,

2-(2-trifluoromethyl-benzenesulfonyl)-4-piperazine-1-base-1H-indoles,

2-benzenesulfonyl-4-(3,5-dimethyl-piperazine-1-yl)-1H-indoles,

2-(3-bromo-benzenesulfonyl)-4-piperazine-1-base-1H-indoles,

2-(thiophene-2-alkylsulfonyl)-4-piperazine-1-base-1H-indoles,

2-(2-fluoro-benzenesulfonyl)-4-(4-methyl-piperazine-1-yl)-1H-indoles,

2-(2-fluoro-benzenesulfonyl)-1-methyl-4-piperazine-1-base-1H-indoles,

2-(3-bromo-benzenesulfonyl)-1-methyl-4-piperazine-1-base-1H-indoles,

2-benzenesulfonyl-4-piperidin-4-yl-1H-indoles.

9. the method for the 2-substituted indole of preparation formula I:

Wherein:

N is 1 or 2;

P is 1 or 2;

R ¹Be phenyl or thienyl, it is chosen wantonly and is replaced by one or more substituting groups, and described substituting group is selected from C ₁-C ₁₂Alkyl, halogen, halo C ₁-C ₁₂Alkyl;

R ²Be piperazinyl or piperidyl, it is optional by one or more C ₁-C ₁₂Alkyl replaces;

R ³Be hydrogen, C ₁-C ₁₂Alkyl; And

Each R ⁴Be hydrogen independently;

Described method comprises:

Make the substituted indole of formula II:

R wherein ², R ⁴, p as defined in claim 1, its optional protected base protection; R ^{3 '}Be C ₁-C ₁₂Alkyl,

(i) and alkali reaction, generate the indoles that takes off proton; With

(ii) making the indoles that takes off proton and Y wherein is the formula of halogen: Y-SO ₂-R ¹Sulfonyl agent reaction or and formula: R ¹-S-S-R ¹The disulphide reagent react, generate the 2-substituted indole of formula III:

R wherein ¹, R ², R ⁴, p as defined in claim 1, R ^{3 '}Be C ₁-C ₁₂Alkyl;

(iii) randomly sulphur is used the oxygenant oxidation; And

(iv) randomly remove protecting group, the 2-substituted indole of production I.

10. the method for claim 19, wherein Y is a fluorine.

11. comprise the formula I compound of the claim 1 to 8 for the treatment of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier.

12. each one or more compounds are in the purposes of preparation in the medicine in the claim 1 to 8, the morbid state that described medicine is used for the treatment of or prevents to be alleviated by the 5-HT6 agonist.

13. the purposes of claim 12, morbid state wherein comprises central nervous system disorders.

14. the purposes of claim 13, morbid state wherein comprises psychosis, schizophrenia, manic depressive illness, neurological disorder, dysmnesia, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease and Huntington Chorea.

15. the purposes of claim 12, morbid state wherein comprises gastrointestinal disorder.

16. the purposes of claim 12, morbid state wherein comprises obesity.